As body mass increases during development, the body adapts to external mechanical loading by increasing the size of the functional units through a process termed mechanochemical transduction. Under normal physiological conditions, tissues found in mammals (such as the eye, blood vessels, lungs and skin) are under tension or residual stress. A dynamic loading pattern that stimulates mechanochemical transduction through the phosphorelay pathways is set up by tension at the tissue-cellular interface. The phosphorelay pathways control cell replication and protein synthesis in mammals. A number of studies have shown that changes in the mechanical properties of tissues accompany the onset and progression of several diseases (e.g., atherosclerosis, cirrhosis, glaucoma, and cancer).
Conventional Methods Used to Measure Mechanical Forces in Tissues
A number of methods have been used to study the mechanical properties of tissues. These methods include constant rate-of-strain, stress-relaxation, dynamic cyclic loading and other techniques many of which permanently destroy the tissue. In general, soft tissues or non-mineralized Extra-Cellular Matrices (“ECMs”) (such as arterial wall, skin and tendon) have moduli between 1 and 2500 MPa. These values depend on the collagen orientation, collagen content, donor age, donor species and anatomical location from which samples are derived. In addition, Poisson's ratio (a parameter used in calculating the modulus in many of the studies using non-invasive techniques) is reported to vary from 0.125 for nucleus pulposis to 1.87 for the surface zone of human patellar cartilage.
Techniques such ultrasonography, elastography and vibrational analysis can be used without destroying the subject tissue. The results of these techniques produce results that do not match the results obtained with destructive techniques. Several studies have reported a value of the elastic modulus of about 20 kPa, which is much lower than is recognized in the scientific literature for ECMs.
Results of other studies have yielded important information concerning the stress-strain behaviors of tissues under different loading conditions. However, technical considerations (such as using a value of about 0.5 for Poisson's ratio) have resulted in values for the modulus that are dramatically different than the values reported using destructive techniques.
Problems exist which are associated with: (1) permanently damaging materials and tissues that are being tested; (2) use of values for mechanical parameters that are difficult to simulate accurately; and (3) difficulty properly interpreting the results of non-invasive methods. These problems lead to the need to develop new methods for analyzing the properties of materials and tissues.
Non-Invasive Studies Involving the Use of Acoustic Mechanical Waves
U.S. Pat. No. 4,646,754 to Seale (“the '754 patent”) describes a non-invasive system for inducing vibrations in a selected element of the human body and detecting the nature of the responses for determining mechanical characteristics. The method described develops a mathematical model of the structure using adjustable parameters to make a fit of the data. The use of adjustable parameters in this approach is of concern.
Non-patent literature entitled “Vibrational Analysis Of Tendon, Mechanical Properties” written by Revel et al. (“Revel”) describes the use of a small hammer and a laser vibrometer to measure the vibrational velocity of an Achilles tendon during uniaxial tensile testing. This document reports a first resonant frequency of 47 to about 57 Hz for stress levels up to about 7 MPa. A conclusion is made in the document that the first resonant frequency is a valued parameter for measurement of some physiological characteristics of tendon. However, the resonant frequencies appear to be very low for tendon considering the modulus of Achilles tendon is expected to be high.
U.S. Pat. No. 7,731,661 to Salcudean et al. (“the '661 patent”) describes a method for applying a vibration signal to a region of tissue, measuring a response to a vibration at a plurality of locations and providing a model of the localized properties of a region of interest. The use of a poorly described model to interpret the results makes this approach less than useful.
U.S. Pat. No. 7,744,535 to Vanderby et al. (“the '535 patent”) describes an ultrasound system for measuring strain subject to varying tension. The ultrasound system implements a process that calculates the strain and stiffness from the time of flight of the sound. However, the time of flight is dependent on the tissue density and modulus, which can only be estimated using this method.
U.S. Pat. No. 7,753,847 to Greenleaf et al. (“the '847 patent”) describes a method for measuring mechanical properties of a subject. Such measurement is achieved by: applying ultrasonic vibration pulses in an on-off time sequence; measuring characteristics of detected harmonic signals; and calculating the mechanical properties using the measured characteristics. This document reports an elasticity of 20 kPa for cirrhosis of the liver. This 20 kPa value is only a fraction of that reported for collagenous tissues and seems rather low.
U.S. Pat. No. 7,946,180 to Sumi (“the '180 patent”) shows an apparatus for storage of one strain tensor, strain-rate data, and pulse wave velocity vector data so that an elastic constant can be calculated. Again the calculations in this approach require modeling that may lead to large errors in the mechanical properties.
U.S. Pat. No. 8,167,804 to Kim et al. (“the '804 patent”) discloses a method for monitoring vascular wall compliance by measuring the pulse wave velocity, the intramural strain and pulse wave velocity. This technique uses an assumed Poisson's ratio of 0.5 to calculate mechanical parameters. The use of an assumed Poisson's ratio is a problem in this approach.
U.S. Pat. No. 8,323,199 to Salcudean et al. (“the '199 patent”) discloses an apparatus for imaging mechanical properties of a tissue region from within an endocavity. Images are collected after a probe is inserted in a cavity and the probe is vibrated using ultrasound. It is unclear in the '199 patent how the images are translated into mechanical properties using this method.
U.S. Patent Publication No. 2014/005548 to Douglas et al. (“the '548 patent publication”) describes an ultrasonic diagnostic imaging system for shear wave analysis using an ultrasonic array probe having a 2-D array of transducer elements. The stiffness is measured by tracking the shear wave front over time. It is unclear how modulus values obtained using this technique compare to the values reported in the literature.
U.S. Patent Publication No. 2014/0081138 to Bercoff et al. (“the '138 patent publication”) discloses a method for measuring a mean viscoelastic value of a soft material using a single probe with at least one transducer. The mean value is estimated by: inducing a constraint zone; measuring a displacement of the zone and of a zone away from the constraint zone; and determining a mean viscoelasticity of tissue displacement between the zones. It is unclear how the viscoelastic parameters measured using this approach compare with values reported in the literature
Non-patent literature entitled “A Review Of Optical Coherence Elastography: Fundamentals, Techniques And Prospects” written by Kennedy et al. (“Kennedy”) reviews Optical Coherence Elastography (“OCE”) as a means to estimate the mechanical properties of tissues. In this document, assumptions are used that are inherent to analyzing acoustic vibrational data using similar techniques. The assumptions used in the studies reviewed include: (1) that a tissue is a linear solid with isotropic properties; (2) that measurement of the resulting displacement from loading with an acoustical wave can be used to estimate a mechanical property; (3) that viscoelastic considerations may not significantly affect the use of classical derivations of constitutive relationships between stress and strain; and (4) that the assumption of incompressibility (Poisson's ratio of about 0.5) will not cause significant calculation errors. The assumption that viscoelastic considerations do not affect the relationship between stress and strain does not agree with the literature results that the viscous contribution to the behavior of tissues such as skin can be as high as 50%.
U.S. Pat. No. 9,043,156 to Gallippi et al. (“the '156 patent”) describes a method for determining the mechanical property parameter of sample by applying acoustic energy. The resulting mechanical property parameter requires the measurement of a response to acoustic energy application and the recovery response, as well as a determination of an additional mechanical parameter based on mathematical relationship between three (3) mechanical parameters. The limitation of this method is that it requires three (3) separate measurements and the result is an estimated elastic modulus.